Non-coding RNA 7SK drives tumor resistance by coupling local oncogenic activation with global transcriptional repression.
The conserved non-coding RNA 7SK is a well-established global transcriptional repressor, yet its context-specific functions in cancer and therapy resistance remain paradoxical. Here, we resolve this paradox by uncovering a dual-axis mechanism through which 7SK drives colorectal cancer (CRC) resistance. By integrating single-cell multi-omics with functional assays, we demonstrate that 7SK not only selectively activates the JUN transcriptional network to fuel tumor proliferation but also reduces global transcriptional entropy to stabilize an immunosuppressive microenvironment and promote immune escape. This "local activation-global suppression" paradigm is conserved across multiple cancer types, positioning 7SK as a potential pan-cancer therapeutic target. Our findings reveal 7SK as a dynamic modulator that balances oncogene-specific transcription with global transcriptional suppression across cancers, providing a new framework for understanding and targeting ncRNA-mediated resistance.